Novel triazole compounds as transforming growth factor (TGF) inhibitors

ABSTRACT

Novel triazole compounds, including derivatives thereof, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use are described. The compounds of the present invention are potent inhibitors of transforming growth factor (“TGF”)-β signaling pathway. They are useful in the treatment of various TGF-related disease states including, for example, cancer and fibrotic diseases.

RELATED APPLICATIONS

This application claims benefit of priority under 35 U.S.C 119(e) toU.S. Provisional Application Nos. 60/412,079 filed on Sep. 18, 2002 and60/484,535 filed on Jul. 2, 2003, each of which is herein incorporatedin its entirety by reference.

BACKGROUND OF THE INVENTION

The present invention relates to novel triazole compounds, includingderivatives thereof, to intermediates for their preparation, topharmaceutical compositions containing them and to their medicinal use.The compounds of the present invention are potent inhibitors of thetransforming growth factor (“TGF”)-β signaling pathway. They are usefulin the treatment of TGF-β related disease states including, for example,cancer and fibrotic diseases.

TGF-β activates both antiproliferative and tumor-promoting signalingcascades. Three mammalian TGF-β isoforms have been identified (TGF-βI,-βII, and -βIII). TGF-β production promotes tumor progression while itsblockade enhances antitumor activity. Blockade of TGF-β enhancesantitumor immune responses and inhibits metastasis. Thus there exists aneed in the art for compounds that inhibit the TGF-β signaling pathway.The present invention, as described below, answers such a need.

SUMMARY OF THE INVENTION

The present invention provides a novel compound containing a coretriazole ring substituted with at least one substituted or unsubstituted2-pyridyl moiety and at least one R¹ moiety, as set forth herein, andall pharmaceutically acceptable salts, prodrugs, tautomers, hydrates andsolvates thereof. In a compound of the invention, the substituted orunsubstituted 2-pyridyl moiety and R¹ moiety can be in an 1,2-, 1,3- or1,4-relationship around the core triazole ring; preferably, in an 1,2-or ortho relationship.

The present invention provides a compound of the formula (Ia), (Ib), or(Ic):

and all pharmaceutically acceptable salts, prodrugs, tautomers, hydratesand solvates thereof, where R¹, R³, R⁶, and s are each as set forthbelow,

with the proviso that R¹ is not a naphthyl or phenyl; and

with the proviso that when R¹ is a phenyl fused with an aromatic ornon-aromatic cyclic ring of 5-7 members containing up to three N atoms,said N is other than —NH or —NC₁₋₆alkyl or if said N is —NH or—NC₁₋₆alkyl, then R¹ must be further substituted; and

with the proviso that when R¹ is a phenyl fused with an aromatic ornon-aromatic cyclic ring of 5-7 members containing 1-3 heteroatomsindependently selected from O and S, then R¹ must be furthersubstituted.

In formulae (Ia), (Ib) and (Ic), each as set forth above:

R¹ is a saturated, unsaturated, or aromatic C₃-C₂₀ mono-, bi- orpolycyclic ring optionally containing at least one heteroatom selectedfrom the group consisting of N, O and S, wherein R¹ can optionally befurther independently substituted with at least one moiety independentlyselected from the group consisting of: carbonyl, halo, halo(C₁-C₆)alkyl,perhalo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy, oxo, mercapto, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy,(C₅-C₁₀)aryl or (C₅-C₁₀)heteroaryl, (C₅-C₁₀)aryloxy or(C₅-C₁₀)heteroaryloxy, (C₅-C₁₀)ar(C₁-C₆)alkyl or(C₅-C₁₀)heteroar(C₁-C₆)alkyl, (C₅-C₁₀)ar(C₁-C₆)alkoxy or(C₅-C₁₀)heteroar(C₁-C₆)alkoxy, HO—(C═O)—, ester, amido, ether, amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₅-C₁₀)heterocyclyl(C₁-C₆)alkyl,(C₁-C₆)alkyl- and di(C₁-C₆)alkylamino, cyano, nitro, carbamoyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylaminocarbonyl,di(C₁-C₆)alkylaminocarbonyl, (C₅-C₁₀)arylcarbonyl,(C₅-C₁₀)aryloxycarbonyl, (C₁-C₆)alkylsulfonyl, and (C₅-C₁₀)arylsulfonyl;

preferably, R¹ can optionally be further independently substituted withzero to two moieties independently selected from the group consistingof, but not limited to, halo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl,perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₅-C₁₀)ar(C₁-C₆)alkoxy or (C₅-C₁₀)heteroar(C₁-C₆)alkoxy, amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and (C₅-C₁₀)heterocyclyl(C₁-C₆)alkyl;

each R³ is independently selected from the group consisting of:hydrogen, halo, halo(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl, (C₅-C₁₀)heteroaryl,(C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₅-C₁₀)heteroaryl-O—,(C₅-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, O₂N—, NC—, amino,Ph(CH₂)₁₋₆HN—, (C₁-C₆)alkyl HN—, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, amino(C═O)—, aminoO₂S—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl(C═O)—[(((C₁-C₆)alkyl)-N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)-N]—, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₅-C₁₀)heteroaryl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(CO)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, ((C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)— and(C₁-C₆)alkyl-(C═O)—O—; preferably, R³ is hydrogen or (C₁-C₆)alkyl; morepreferably, R³ is hydrogen or methyl;

where alkyl, alkenyl, alkynyl, phenyl, heteroaryl, heterocyclic,cycloalkyl, alkoxy, phenoxy, amino of R³ is optionally substituted by atleast one substituent independently selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo, H₂N—, Ph(CH₂)₁₋₆HN—, and(C₁-C₆)alkylHN—;

s is an integer from one to five; preferably, one to two; morepreferably, one; and

R⁶ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, (C₅-C₁₀)heteroaryl,(C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-(SO₂)—,phenyl-(SO₂)—, H₂N—(SO₂)—, (C₁-C₆)alkyl-NH—(SO₂)—,((C₁-C₆)alkyl)₂N—(SO₂)—, phenyl-NH—(SO₂)—, (phenyl)₂N—(SO₂)—,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₅-C₁₀)heteroaryl(C═O)—,(C₅-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₅-C₁₀)heterocyclic-O-(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,phenyl-NH—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,((C₁-C₆)alkyl)₂N—(C═O)—, (phenyl)₂N—(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O),(C₅-C₁₀)heteroaryl-[((C₁-C₆)alkyl)-N]—(C═O)—,(C₅-C₁₀)heterocyclic-[((C₁-C₆)alkyl)-N]—(C═O)—, and(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)-N]—(C═O)—; preferably, R⁶ ishydrogen, (C₁-C₆)alkyl, or (C₃-C₁₀)cycloalkyl;

where alkyl, alkenyl, alkynyl, phenyl, benzyl, heteroaryl, heterocyclic,cycloalkyl, alkoxy, phenoxy, amino of R⁶ is optionally substituted withat least one moiety independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, benzyl, (C₅-C₁₀)heterocyclic,(C₅-C₁₀)heteroaryl, (C₁-C₆)alkyl-SO₂—, formyl, NC—, (C₁-C₆)alkyl-(C═O)—,(C₃C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₅-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₅-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,((C₁-C₆)alkyl)₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₅-C₁₀)heterocyclic-O—, (C₅-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₅-C₁₀)heterocyclic-(C═O)—O—, (C₅-C₁₀)heteroaryl(C═O)—O—, O₂N—, amino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₅-C₁₀)heterocyclic-(C═O)—NH—, (C₅-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—, phenyl-(C═O)—[(C₁-C₆)alkyl-N]—,(C₁-C₆)alkyl-SO₂NH—, (C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—,(C₅-C₁₀)heterocyclic-SO₂NH— and (C₅-C₁₀)heteroaryl-SO₂NH—; preferably,R⁶is substituted with zero to two groups independently selected from thegroup consisting of (C₁-C₆)alkyl and (C₃-C₁₀)cycloalkyl;

wherein the phenyl or heteroaryl moiety of a R⁶ substituent isoptionally further substituted with at least one radical independentlyselected from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,perfluoro(C₁-C₆)alkyl and perfluoro(C₁-C₆)alkoxy.

In another embodiment of the invention, R¹ of formulae (Ia), (Ib) and(Ic), each as set forth above, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formulae (Ia), (Ib) and(Ic), each as set forth above, is

In another embodiment of the invention, R¹ of formulae (Ia), (Ib) and(Ic), each as set forth above, is

In another embodiment of the invention, R¹ of formulae (Ia), (Ib) and(Ic), each as set forth above, is

In another embodiment of the invention, R¹ of formulae (Ia), (Ib) and(Ic), each as set forth above, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formulae (Ia), (Ib) and(Ic), each as set forth above, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formulae (Ia), (Ib) and(Ic), each as set forth above, is

where R^(2a) is as set forth herein.

Each of R¹ above can optionally be further substituted by at least oneR^(2a) group, as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

where R^(2a) is as set forth herein.

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), as set forthabove, is

In another embodiment of the invention, R¹ of formula (Ia), (Ib) or(Ic), each as set forth above, is

where R^(2a) is as set forth herein and where the proviso language doesnot apply.

In another embodiment of the invention, R¹ of formula (Ia), (Ib) or(Ic), each as set forth above, is selected from the group consisting of:

and where the proviso language does not apply.

In another embodiment of the invention R¹ of formula (Ia), (Ib) or (Ic),each as set forth above, is selected from the group consisting of:

and and where the proviso language does not apply.

In another embodiment of the invention, R¹ of formula (Ia), (Ib) or(Ic), each as set forth above, is selected from the group consisting of:

where R^(2a) is as set forth herein and where the proviso language doesnot apply.

The invention also provides a pharmaceutical composition comprising atleast one compound of the invention and a pharmaceutically acceptablecarrier.

The invention further provides a method of preparation of a compound ofthe invention.

The invention still further provides a method of preventing or treatinga TGF-related disease state in an animal or human comprising the step ofadministering a therapeutically effective amount of at least onecompound of the invention to the animal or human suffering from theTGF-related disease state.

The invention still further provides the use of a compound of theinvention in the preparation of a medicament for the prevention ortreatment of a TGF-related disease state in an animal or human.

DEFINITIONS

As used herein, the article “a” or “an” refers to both the singular andplural form of the object to which it refers.

As used herein, the term “alkyl,” as well as the alkyl moieties of othergroups referred to herein (e.g., alkoxy) refers to a linear or branchedsaturated hydrocarbon (e.g., methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, secondary-butyl, tertiary-butyl).

As used herein, the term “cycloalkyl” refers to a mono or bicycliccarbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl).

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo or iodo or fluoride, chloride, bromide or iodide.

As used herein, the term “halo-substituted alkyl” or “haloalkyl” refersto an alkyl radical, as set forth above, substituted with one or morehalogens, as set forth above, including, but not limited to,chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, and 2,2,2-trichloroethyl.

As used herein, the term “perhaloalkyl” refers to an alkyl radical, asset forth above, where each hyrdrogen of the alkyl group is replacedwith a “halogen” or “halo”, a set forth above.

As used herein, the term “alkenyl” refers to a linear or branchedhydrocarbon chain radical containing at least two carbon atoms and atleast one double bond. Examples include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl(allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

As used herein, the term “alkynyl” refers to a linear or branchedhydrocarbon chain radical having at least one triple bond including, butnot limited to, ethynyl, propynyl, and butynyl.

As used herein, the term “carbonyl” refers to a >C═O moiety.Alkoxycarbonylamino (i.e. alkoxy(C═O)—NH—) refers to an alkyl carbamategroup. The carbonyl group is also equivalently defined herein as (C═O).

As used herein, the term “phenyl-[(alkyl)-N]—(C═O)—” refers to aN,N′-disubstituted amide group of the formula

As used herein, the term “aryl” refers to an aromatic radical such as,for example, phenyl, naphthyl, tetrahydronaphthyl, and indanyl.

As used herein, the term “heteroaryl” refers to an aromatic groupcontaining at least one heteroatom selected from O, S and N. Forexample, heteroaryl groups include, but are not limited to, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl,pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g.,1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g.,1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl,isoquinolyl, benzothienyl, benzofuryl, and indolyl.

As used herein, the term “heterocyclic” refers to a saturated orunsaturated C₃-C₂₀ mono-, bi- or polycyclic group containing at leastone heteroatom selected from N, O, and S. Examples of heterocyclicgroups include, but are not limited to, azetidinyl, tetrahydrofuranyl,imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl,thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl,tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl,oxazinyl, oxcithiazinyl, indolinyl, isoindolinyl, quincuclidinyl,chromanyl, isochromanyl, benzocazinyl, and the like. Examples ofmonocyclic saturated or unsaturated ring systems aretetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl,isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,and 1,2,5-oxathiazin-4-yl.

As used herein, the term “pharmaceutically acceptable acid additionsalt” refers to non-toxic acid addition salts, i.e., salts derived frompharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-2-hydroxy-3-naphthoate)]salts.

As used herein, the term “pharmaceutically acceptable base additionsalt” refers to non-toxic base addition salts, i.e., salts derived fromsuch pharmacologically acceptable cations such as alkali metal cations(e.g. potassium and sodium) and alkaline earth metal cations (e.g.,calcium and magnesium), ammonium or water-soluble amine addition saltssuch as N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines.

As used herein, the term “suitable substituent”, “substituent” or“substituted” refers to a chemically and pharmaceutically acceptablefunctional group, ie., a moiety that does not negate the inhibitoryand/or therapeutic activity of the inventive compounds. Such suitablesubstituents may be routinely selected by those skilled in the artIllustrative examples of suitable substituents include, but are notlimited to, carbonyl, halo, haloalkyl, perfluoroalkyl, perfluoroalkoxy,alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, arylor heteroaryl, aryloxy or heteroaryloxy, aralkyl or heteroaralkyl,aralkoxy or heteroaralkoxy, HO—(C═O)—, ester, amido, ether, amino,alkyl- and dialkylamino, cyano, nitro, carbamoyl, alkylcarbonyl,alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl,aryloxycarbonyl, alkylsulfonyl, arylsulfonyl and the like. Those skilledin the art will appreciate that many substituents can be substituted byadditional substituents.

As used herein, the term “TGF-related disease state” refers to anydisease state mediated by the production of TGF-β.

As used herein, the term “Ph” refers to phenyl.

As used herein, the term “a saturated, unsaturated, or aromatic C₃-C₂₀mono-, bi- or polycyclic ring optionally containing at least oneheteroatom” refers to, but is not limited to,

where R^(2a) is independently selected from the group consisting of:(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₁₀)cycloalkyl,(C₅-C₁₀)aryl, (C₁-C₆)alkylaryl, amino, carbonyl, carboxyl, (C₂-C₆)acid,(C₁-C₆)ester, (C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclyl, (C₁-C₆)alkoxy,nitro, halo, hydroxyl, (C₁-C₆)alkoxy(C₁-C₆)ester, and those groupsdescribed in U.S. application Ser. Nos. 10/094,717, 10/094,760, and10/115,952, each of which is herein incorporated in its entirety byreference; and where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, amino,acid, ester, heteroaryl, heterocyclyl, and alkoxy of R^(2a) isoptionally substituted by at least one moiety independently selectedfrom the group consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl, (C₃-C₁₀)cycloalkyl,(C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclic, formyl, NC—,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, ((C₁-C₆)alkyl)₂—N—(C═O)—, phenyl-NH(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, O₂N—, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂-amino, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)-N]—, H₂N—(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—NH—, ((C₁-C₆)alkyl)₂N—(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—[((C₁-C₆)alkyl)-N]—,((C₁-C₆)alkyl)₂N—(C═O)—[(C₁-C₆)alkyl-N]—, phenyl-HN—(C═O)—NH—,(phenyl)₂N—(C═O)—NH—, phenyl-HN—(C═O)—[((C₁-C₆)alkyl)-N]—,(phenyl-)₂N—(C═O)—[((C₁-C₆)alkyl)-N]—, (C₁-C₆)alkyl-O—(C═O)—NH—,(C₁-C₆)alkyl-O—(C═O)—[((C₁-C₆)alkyl)-N]—, phenyl-O-(C═O)—NH—,phenyl-O—(C═O)—[(alkyl)-N]—, (C₁-C₆)alkyl-SO₂NH—, phenyl-SO₂NH—,(C₁-C₆)alkyl-SO₂—, phenyl-SO₂—, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)ester-(C₁-C₆)alkyl-O—, phenyl-(C═O)—O—, H₂N—(C═O)—O—,(C₁-C₆)alkyl-HN—(C═O)—O—, ((C₁-C₆)alkyl)₂N—(C═O)—O—, phenyl-HN—(C═O)—O—,and (phenyl)₂N—(C═O)—O—.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction schemes illustrate the preparation of thecompounds of the present invention. A compound of the invention may beprepared by methods analogous to those described in U.S. applicationSer. Nos. 10/094,717, 10/094,760, and 10/115,952 and WO 02/40476. Unlessotherwise indicated, R¹, R³, R⁶, R^(2a) and s in the reaction schemesand the discussion that follow are defined above.

Scheme I refers to the preparation of compounds of the formulae Ia, Iband Ic. Referring to Scheme I, a compound of formula III was preparedfrom a compound of formula II by combining the compound with a catalystsuch as PdCl₂(PPh)₂, in the presence of an additive such as CuI, andethynyl-trimethyl-silane, at a temperature of about 0° C. to about 80°C., preferably about room temperature, in a polar solvent such astetrahydrofuran. The compound of formula V was prepared from compoundIII by treatment with a base such as potassium carbonate, in a polarsolvent such as methanol. Subsequent combining with a catalyst (such aspalladium tetrakis), an additive (such as CuI), and a compound offormula IV, in a polar solvent such as tetrahydrofuran with anadditional polar solvent such as tetramehtylethylenediamine, at atemperature of about 20° C. to about 100° C., preferably about 55° C.The compound of formula VI was prepared from compound V by treatmentwith trimethylsilylazide at a temperature of about 20° C. to about 160°C., preferably about 130° C., in a polar solvent such asdimethylformamide. The compounds of formulae Ia, Ib, and Ic are preparedfrom the compound of formula VI by treatment with a base such aspotassium carbonate, and an alkyl halide R⁶X, in a polar solvent such asacetonitrile.

Preparation A refers to the preparation of compounds of the formula VIIIwhich are intermediates in the preparation of compounds of the formula(Ia), (Ib) and (Ic) in Scheme 1. Referring to preparation A, compoundsof formula VIII (equivalent to a compound of formula II of Scheme 1) areprepared as described in the literature (Moran, D. B.; Morton, G. O.;Albright, J. D., J. Heterocycl. Chem., Vol. 23, pp. 1071-1077 (1986)) orfrom compounds of formula VII wherein L′ is chloride, bromide or iodide,by reaction with hydrazine. A compound of formula VIII was prepared froma compound of formula VII with a cyclization reagent such as acidchloride, acid anhydride, trialkylorthoacetate or trialkylorthoformate.Compounds of formula VI are commercially available.

All pharmaceutically acceptable salts, prodrugs, tautomers, hydrates andsolvates of a compound of the invention is also encompassed by theinvention.

A compound of the invention which is basic in nature is capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals and humans, it is often desirable inpractice to initially isolate a compound of the invention from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent, and subsequently convert the free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent such as, for example, methanol or ethanol. Upon carefulevaporation of the solvent, the desired solid salt is obtained.

The acids which can be used to prepare the pharmaceutically acceptableacid addition salts of the base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as chloride, bromide, iodide,nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate,lactate, citrate or acid citrate, tartrate or bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate andpamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

A compound of the invention which is also acidic in nature, e.g.,contains a COOH or tetrazole moiety, is capable of forming base saltswith various pharmacologically acceptable cations. Although such saltsmust be pharmaceutically acceptable for administration to animals andhumans, it is often desirable in practice to initially isolate acompound of the invention from the reaction mixture as apharmaceutically unacceptable salt and then simply convert the latterback to the free acid compound by treatment with an acidic reagent, andsubsequently convert the free acid to a pharmaceutically acceptable baseaddition salt. Examples of such pharmaceutically acceptable baseaddition salts include the alkali metal or alkaline-earth metal saltsand particularly, the sodium and potassium salts. These salts can beprepared by conventional techniques. The chemical bases which can beused as reagents to prepare the pharmaceutically acceptable baseaddition salts of this invention are those which form non-toxic basesalts with the herein described acidic compounds of the invention. Thesenon-toxic base salts include salts derived from such pharmacologicallyacceptable cations as sodium, potassium, calcium and magnesium, etc.These salts can easily be prepared by treating the corresponding acidiccompounds with an aqueous solution containing the desiredpharmacologically acceptable cations, and then evaporating the resultingsolution to dryness, preferably under reduced pressure. Alternatively,they may also be prepared by mixing lower alkanolic solutions of theacidic compounds and the desired alkali metal alkoxide together, andthen evaporating the resulting solution to dryness in the same manner asbefore. In either case, stoichiometric quantities of reagents arepreferably employed in order to ensure completeness of reaction andmaximum product yields.

Isotopically-labeled compounds are also encompassed by the presentinvention. As used herein, an “isotopically-labeled compound” refers toa compound of the invention including pharmaceutical salts, prodrugsthereof, each as described herein, in which one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

By isotopically-labeling a compound of the present invention, thecompounds may be useful in drug and/or substrate tissue distributionassays. Tritiated (³H) and carbon-14 (¹⁴C) labeled compounds areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium (²H) canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of the invention, includingpharmaceutical salts, prodrugs thereof, can be prepared by any meansknown in the art.

Stereoisomers (e.g., cis and trans isomers) and all optical isomers of acompound of the invention (e.g., R and S enantiomers), as well asracemic, diastereomeric and other mixtures of such isomers arecontemplated by the present invention.

The compounds, salts, prodrugs, tautomers, hydrates, and solvates of thepresent invention can exist in several tautomeric forms, including theenol and imine form, and the keto and enamine form and geometric isomersand mixtures thereof. All such tautomeric forms are included within thescope of the present invention. Tautomers exist as mixtures of atautomeric set in solution. In solid form, usually one tautomerpredominates. Even though one tautomer may be described, the presentinvention includes all tautomers of the present compounds.

The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of the invention that can beseparated into rotationally restricted isomers.

A compound of the invention, as described above, can be used in themanufacture of a medicament for the prophylactic or therapeutictreatment of a TGF-related disease state in an animal or human.

A compound of the invention is a potent inhibitor of transforming growthfactor (“TGF”)-β signaling pathway and are therefore of use in therapy.Accordingly, the present invention provides a method of preventing ortreating a TGF-related disease in an animal or human comprising the stepof administering a therapeutically effective amount of at least onecompound of the invention to the animal or human suffering from theTGF-related disease state.

As used herein, the term “therapeutically effective amount” refers to anamount of a compound of the invention required to inhibit the TGF-βsignaling pathway. As would be understood by one of skill in the art, a“therapeutically effective amount” will vary from patient to patient andwill be determined on a case by case basis. Factors to consider include,but are not limited to, the patient being treated, weight, health,compound administered, etc.

There are numerous disease states that can be treated by inhibition ofthe TGF-β signaling pathway. Such disease states include, but are notlimited to, all types of cancer (e.g., breast, lung, colon, prostate,ovarian, pancreatic, melanoma, all hematological malignancies, etc.) aswell as all types of fibrotic diseases (e.g., glomerulonephritis,diabetic nephropathy, hepatic fibrosis, pulmonary fibrosis, arterialhyperplasia and restenosis, scleroderma, and dermal scarring).

The present invention also provides a pharmaceutical compositioncomprising at least one compound of the invention and at least onepharmaceutically acceptable carrier. The pharmaceutically acceptablecarrier may be any such carrier known in the art including thosedescribed in, for example, Remington's Pharmaceutical Sciences, MackPublishing Co., (A. R. Gennaro edit. 1985). A pharmaceutical compositionof the invention may be prepared by conventional means known in the artincluding, for example, mixing at least one compound of the inventionwith a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention may be used in theprevention or treatment of a TGF-related disease state, as describedabove, in an animal or human. Thus, a compound of the invention may beformulated as a pharmaceutical composition for oral, buccal, intranasal,parenteral (e.g., intravenous, intramuscular or subcutaneous), topical,or rectal administration or in a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical composition may take theform of, for example, a tablet or capsule prepared by conventional meanswith a pharmaceutically acceptable excipient such as a binding agent(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); filler (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricant (e.g., magnesium stearate,talc or silica); disintegrant (e.g., potato starch or sodium starchglycolate); or wetting agent (e.g., sodium lauryl sulphate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of a, for example, solution, syrupor suspension, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means with apharmaceutically acceptable additive such as a suspending agent (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicle (e.g.,almond oil, oily esters or ethyl alcohol); and preservative (e.g.,methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

A compound of the present invention may also be formulated for sustaineddelivery according to methods well known to those of ordinary skill inthe art. Examples of such formulations can be found in U.S. Pat. Nos.3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397, which areherein incorporated by reference in their entirety.

A compound of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain a formulating agent such as a suspending,stabilizing and/or dispersing agent. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

A compound of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, acompound of the invention may be conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the compound of theinvention. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of a compound of the invention for oral, parenteral orbuccal administration to the average adult human for the treatment of aTGF-related disease state is about 0.1 mg to about 2000 mg, preferably,about 0.1 mg to about 200 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to abovein the average adult human are preferably arranged so that each metereddose or “puff” of aerosol contains about 20 μg to about 10,000 μg,preferably, about 20 μg to about 1000 μg of a compound of the invention.The overall daily dose with an aerosol will be within the range fromabout 100 μg to about 100 mg, preferably, about 100 μp to about 10 mg.Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

Aerosol combination formulations for treatment of the conditionsreferred to above in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains from about 0.01 mgto about 1000 mg, preferably, about 0.01 mg to about 100 mg of acompound of this invention, more preferably from about 1 mg to about 10mg of such compound. Administration may be several times daily, forexample 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses eachtime.

Aerosol formulations for treatment of the conditions referred to abovein the average adult human are preferably arranged so that each metereddose or “puff” of aerosol contains from about 0.01 mg to about 20,000mg, preferably, about 0.01 mg to about 2000 mg of a compound of theinvention, more preferably from about 1 mg to about 200 mg.Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

For topical administration, a compound of the invention may beformulated as an ointment or cream.

This invention also encompasses pharmaceutical compositions containingand methods of treatment or prevention comprising administering prodrugsof at least one compound of the invention. As used herein, the term“prodrug” refers to a pharmacologically inactive derivative of a parentdrug molecule that requires biotransformation, either spontaneous orenzymatic, within the organism to release the active drug. Prodrugs arevariations or derivatives of the compounds of this invention which havegroups cleavable under metabolic conditions. Prodrugs become thecompounds of the invention which are pharmaceutically active in vivo,when they undergo solvolysis under physiological conditions or undergoenzymatic degradation. Prodrug compounds of this invention may be calledsingle, double, triple etc., depending on the number ofbiotransformation steps required to release the active drug within theorganism, and indicating the number of functionalities present in aprecursor-type form. Prodrug forms often offer advantages of solubility,tissue compatibility, or delayed release in the mammalian organism (see,Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp.352-401, Academic Press, San Diego, Calif., 1992). Prodrugs commonlyknown in the art include acid derivatives well known to practitioners ofthe art, such as, for example, esters prepared by reaction of the parentacids with a suitable alcohol, or amides prepared by reaction of theparent acid compound with an amine, or basic groups reacted to form anacylated base derivative. Moreover, the prodrug derivatives of thisinvention may be combined with other features herein taught to enhancebioavailability. For example, a compound of the invention having freeamino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to freeamino, hydroxy or carboxylic acid groups of compounds of the invention.The amino acid residues include the 20 naturally occurring amino acidscommonly designated by three letter symbols and also include,4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, omithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters which are covalently bonded to the above substituentsof a compound of the invention through the carbonyl carbon prodrugsidechain.

According to the invention, in the treatment of a TGF-related diseasestate, a compound of the invention, as described herein, whether aloneor as part of a pharmaceutical composition may be combined with anothercompound(s) of the invention and/or with another therapeutic agent(s).Examples of suitable therapeutic agent(s) include, but are not limitedto, standard non-steroidal anti-inflammatory agents (hereinafterNSAID's) (e.g, piroxicam, diclofenac), propionic acids (e.g., naproxen,flubiprofen, fenoprofen, ketoprofen and ibuprofen), fenamates (e.g.,mefenamic acid, indomethacin, sulindac, apazone), pyrazolones (e.g.,phenylbutazone), salicylates (e.g., aspirin), COX-2 inhibitors (e.g.,celecoxib, valdecoxib, rofecoxib and etoricoxib), analgesics andintraarticular therapies (e.g., corticosteroids) and hyaluronic acids(e.g., hyalgan and synvisc), anticancer agents (e.g., endostatin andangiostatin), cytotoxic drugs (e.g., adriamycin, daunomycin,cis-platinum, etoposide, taxol, taxotere), alkaloids (e.g.,vincristine), and antimetabolites (e.g., methotrexate), cardiovascularagents (e.g., calcium channel blockers), lipid lowering agents (e.g.,statins), fibrates, beta-blockers, Ace inhibitors, Angiotensin-2receptor antagonists and platelet aggregation inhibitors, CNS agents(e.g., as antidepressants (such as sertraline)), anti-Parkinsonian drugs(e.g., deprenyl, L-dopa, Requip, Mirapex), MAOB inhibitors (e.g.,selegine and rasagiline), comP inhibitors (e.g., Tasmar), A-2inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotineagonists, Dopamine agonists and inhibitors of neuronal nitric oxidesynthase), anti-Alzheimer's drugs (e.g., donepezil, tacrine, COX-2inhibitors, propentofylline or metryfonate), osteoporosis agents (e.g.,roloxifene, droloxifene, lasofoxifene or fosomax), and immunosuppressantagents (e.g., FK-506 and rapamycin).

Biological Activity

The activity of the compounds of the invention for the variousTGF-related disease states as described herein can be determinedaccording to one or more of the following assays. According to theinvention, a compound of the invention exhibits an in vitro IC₅₀ valueof less than about 10 μM. For example, the compound of Example 2exhibits a TβRI IC₅₀ value of about 58 nM.

The compounds of the present invention also possess differentialactivity (i.e. are selective for) for TβRI over TβRII and TβRIII.Selectivity is measured in standard assays as a IC₅₀ ratio of inhibitionin each assay.

TGF-β Type II Receptor (TβRII) Kinase Assay Protocol

Phosphorylation of myelin basic protein (MBP) by the TβRII kinase wasmeasured as follows: 80 microliters of MBP (Upstate Biotechnology#13-104) diluted in kinase reaction buffer (KRB) containing 50 mM MOPS,5 mM MgCl₂, pH 7.2 to yield a final concentration of 3 micromolar MBPwas added to each well of a Millipore 96-well multiscreen-DP 0.65 micronfiltration plate (#MADPNOB50). 20 microliters of inhibitor diluted inKRB was added to appropriate wells to yield the desired finalconcentration (10-0.03 micromolar). 10 microliters of a mixture of ATP(Sigma #A-5394) and ³³P-ATP (Perkin Elmer #NEG/602H) diluted in KRB wasadded to yield a final concentration of 0.25 micromolar ATP and 0.02microcuries of ³³P-ATP per well. 10 microliters of a GST-TβRII fusionprotein (glutathione S-transferase at the N-terminal end of thecytoplasmic domain of TβRII-amino acids 193-567 with A to V change at438) diluted in KRB was added to each well to yield a finalconcentration of 27 nanomolar GST-TβRII. Plates were mixed and incubatedfor 90 minutes at room temperature. After the reaction incubation, 100microliters of cold 20% trichloroacetic acid (Aldrich #25,139-9) wasadded per well and plates were mixed and incubated for 60 minutes at 4°C. Liquid was then removed from the wells using a Millipore vacuummanifold. Plates were washed once with 200 microliters per well of cold10% trichloroacetic acid followed by two washes with 100 microliters perwell of cold 10% trichloroacetic acid. Plates were allowed to dryovernight at room temperature. 20 microliters of Wallac OptiPhaseSuperMix scintillation cocktail was added to each well. Plates weresealed and counted using a Wallac 1450 Microbeta liquid scintillationcounter. The potency of inhibitors was determined by their ability toreduce TβRII-mediated phosphorylation of the MBP substrate.

ALK-5 (TβRI) Kinase Assay Protocol

The kinase assays were performed with 65 nM GST-ALK5 and 84 nM GST-Smad3in 50 mM HEPES, 5 mM MgCl₂, 1 mM CaCl₂, 1 mM dithiothreitol, and 3 _MATP. Reactions were incubated with 0.5 _Ci of [33 P]_ATP for 3 h at 30°C. Phosphorylated protein was captured on P-81 paper (Whatman,Maidstone, England), washed with 0.5% phosphoric acid, and counted byliquid scintillation. Alternatively, Smad3 or Smad1 protein was alsocoated onto FlashPlate Sterile Basic Microplates (PerkinElmer LifeSciences, Boston, Mass.). Kinase assays were then performed inFlash-Plates with same assay conditions using either the kinase domainof ALK5 with Smad3 as substrate or the kinase domain of ALK6 (BMPreceptor) with Smad1 as substrate. Plates were washed three times withphosphate buffer and counted by TopCount (Packard Bio-science, Meriden,Conn.). (Laping, N. J. et al. Molecular Pharmacology 62:58-64 (2002)).

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (d) and are referenced to the deuteriumlock signal from the sample solvent (deuteriochloroform unless otherwisespecified). Mass Spectral data were obtained using a Micromass ZMD APCIMass Spectrometer equipped with a Gilson gradient high performanceliquid chromatograph. The following solvents and gradients were used forthe analysis. Solvent A; 98% water/2% acetonirile/0.01% formic acid andsolvent B; acetonitrile containing 0.005% formic acid. Typically, agradient was run over a period of about 4 minutes starting at 95%solvent A and ending with 100% solvent B. The mass spectrum of the majoreluting component was then obtained in positive or negative ion modescanning a molecular weight range from 165 AMU to 1100 AMU. Specificrotations were measured at room temperature using the sodium D line (589nm). Commercial reagents were utilized without further purification. THFrefers to tetrahydrofuran. DMF refers to N,N-dimethylformamide.Chromatography refers to column chromatography performed using 32-63 mmsilica gel and executed under nitrogen pressure (flash chromatography)conditions. Room or ambient temperature refers to 20-25° C. Allnon-aqueous reactions were run under a nitrogen atmosphere forconvenience and to maximize yields. Concentration at reduced pressuremeans that a rotary evaporator was used.

One of ordinary skill in the art will appreciate that in some casesprotecting groups may be required during preparation. After the targetmolecule is made, the protecting group can be removed by methods wellknown to those of ordinary skill in the art, such as described in Greeneand Wuts, “Protective Groups in Organic Synthesis” (2^(nd) Ed, JohnWiley & Sons 1991).

Analytical high performance liquid chromatography on reverse phase withmass spectrometry detection (LSMS) was done using Polaris 2×20 mm C18column. Gradient elution was applied with increase of concentration ofacetonitrile in 0.01% aqueous formic acid from 5% to 100% during 3.75min period. Mass spectrometer Micromass ZMD was used for molecular ionidentification.

EXAMPLE 1 Preparation of3-Isopropyl-6-[5-(3-methyl-pyridin-2-yl)-2H-[1,2,3]triazol-4-yl]-[1,2,4]triazolo[4,3-a]pyridineStep A: Preparation of3-Isopropyl-6-trimethylsilanylethynyl-[1,2,4]triazolo(4,3-a)pyridine

To a 125 mL round bottom flask was added3-isopropyl-6-Bromo-[1,2,4]triazolo(4,3-a)pyridine (3.51 g, 14.6 mmol, 1equivalent) and 29 mL of dry THF. This solution was bubbled with argongas for 5 minutes. 28 mg (0.15 mmol) of copper iodide, 205 mg (0.3 mmol)of bis(triphenylphosphine)palladium(II)chloride, and 4.13 mL (29.2 mmol,d=0.695) of (trimethylsilyl)acetylene were added. Finally, 4.1 mL (29.2mmol, d=0.722) of diisopropylamine was added drop wise. The reactionmixture was stirred at room temperature and under argon for 24 hours.The reaction mixture was then filtered through celite (packed in ethylacetate) and the celite was washed with 150 mL of ethyl acetate. Thisfiltrate was concentrated, and the residue was suspended in 125 mL ofwater, which was then extracted with (3×70 mL) ethyl acetate. Theorganic extracts were combined, dried over magnesium sulfate, filtered,and concentrated to dryness. The product was then purified by flashcolumn chromatography (Biotage flash 40M silica gel packed cartridge)using a 0 to 10% ethyl acetate/chloroform solvent step-gradient whichyielded 2.5 grams (66%) of a brown solid. HPLC t_(R)=5.73 min (88%),LC-MS=258 (M+1).

Step) B: Preparation of3-Isopropyl-6-ethynyl-[1.2.4,]triazolo(4.3-a)pyridine

To a 250 mL round bottom flask was added 2.5 g (9.71 mmol) of3-Isopropyl-6-trimethylsilanylethynyl-[1,2,4]triazolo(4,3-a) pyridine,50 mL of methanol, and 4.03 g (29.1 mmol) of potassium carbonate. Thissuspension was stirred at room temperature for 2 hours. The reactionmixture was concentrated, and the residue was suspended in 100 mL ofwater, which was extracted with (2×100 mL) ethyl acetate. The organicextracts were combined, washed with 100 mL of a 1:1 solution of brineand water, dried over magnesium sulfate, filtered, and concentrated todryness to yield 1.47 grams (82%) of a light brown solid. HPLCt_(R)=3.22 min (93%), LC-MS=186 (M+1).

Step C: Preparation of3-Isopropyl-6-(6-methylpyridin-2-ylethynyl)-[1,2,4]triazolo(4.3-a)pyridine

To a 250 mL round bottom flask was added 1.47 grams (7.94 mmol) of3-Isopropyl-6-ethynyl-[1,2,4]triazolo(4,3-a)pyridine, 40 mL of anhydrousTHF, 40 mL of TMEDA, 279 mg (0.4 mmol) ofbis(triphenylphosphine)palladium(II)chloride, 151 mg (0.8 mmol) ofcopper iodide, and 1.8 mL (15.9 mmol, d=1.512) of2-bromo-6-methylpyridine. Argon gas was bubbled into the reactionmixture for 5 minutes. The reaction mixture was stirred at 60° C. for 5hours. The reaction mixture was cooled and concentrated to dryness. Theresidue was suspended in a mixture of ethyl acetate and water (80 mLeach) and filtered through celite that was packed with ethyl acetate.The celite was washed with 100 mL of ethyl acetate. After separating theorganic layer, the filtrate was extracted with 50 mL of ethyl acetate.All the organic layers were combined, washed with 100 mL of water, thenwashed with 100 mL of brine, dried over magnesium sulfate, filtered, andconcentrated. Product was purified by flash column chromatography(Biotage flash 40M silica gel packed cartridge) using a 0 to 80% ethylacetate/chloroform solvent step-gradient which yielded 840 milligrams(38%) of an orange syrup. HPLC t_(R)=4.27 min (100%), LC-MS=277 (M+1).

Step D: Preparation of3-Isopropyl-6-[5-(6-methyl-pyridin-2-yl)-1H-[1,2,3]triazol-4-yl]-[1,2,4]triazolo-4,3-a]pyridine

To a 10 mL flask was added 100 mg (0.36 mmol) of3-Isopropyl-6-(6-methylpyridin-2-ylethynyl)-[1,2,4]triazolo(4,3-a)pyridine,1.5 mL of anhydrous DMF, and 168 μL (1.3 mmol) of azidotrimethylsilane.The reaction mixture was heated to reflux for 16 hours. Afterconcentrating, the residue was suspended in 30 mL of water and wasextracted with (2×30 mL) ethyl acetate. The organic extracts werecombined, washed with 20 mL of water, 20 mL of brine, dried overmagnesium sulfate, filtered, and concentrated. Product was purified byShimodzu prep. HPLC using a 5 to 60% acetonitrile/buffer gradient(buffer is water with 0.1% formic acid, and the acetonitrile contains0.1% formic acid as well) which yielded 45 milligrams (39%) of a lightbrown solid. HPLC t_(R)=3.71 min (98%), LC-MS=320 (M+1).

EXAMPLE 23-Methyl-6-[5-(6-methyl-pyridin-2-yl)-2H-[1,2,3]triazol-4-yl]-[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.22 min, LC-MS=292 (M+1).

EXAMPLE 36-[5-(6-Methyl-pyridin-2-yl)-2H-[1,2,3]triazol-4-yl]-quinazoline

The title compound was prepared according to procedures analogous tothose described in Example 1. HPLC t_(R)=3.46 min, LC-MS=289 (M+1).

All publications, including but not limited to, issued patents, patentapplications, and journal articles, cited in this application are eachherein incorporated by reference in their entirety.

Although the invention has been described above with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific experiments detailed are only illustrative of theinvention. Accordingly, the invention is limited only by the followingclaims.

1. A compound of formula (Ia), (Ib), or (Ic):

or a pharmaceutically acceptable salt, prodrug, tautomer, hydrate orsolvate thereof, wherein: R¹ is a saturated, unsaturated, or aromaticC₃-C₂₀ mono-, bi- or polycyclic ring optionally containing at least oneheteroatom selected from the group consisting of N, O and S, wherein R¹can optionally be further independently substituted with at least onemoiety independently selected from the group consisting of: carbonyl,halo, halo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy, oxo, mercapto,(C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₅-C₁₀)aryl or (C₅-C₁₀)heteroaryl,(C₁-C₁₀)aryloxy or (C₅-C₁₀)heteroaryloxy, (C₅-C₁₀)ar(C₁-C₆)alkyl or(C₅-C₁₀)heteroar(C₁-C₆)alkyl, (C₅-C₁₀)ar(C₁-C₆)alkoxy or(C₅-C₁₀)heteroar(C₁-C₆)alkoxy, HO—(C═O)—, ester, amido, ether, amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₅-C₁₀)heterocyclyl(C₁-C₆)alkyl,(C₁-C₆)alkyl- and di(C₁-C₆)alkylamino, cyano, nitro, carbamoyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylaminocarbonyl,di(C₁-C₆)alkylaminocarbonyl, (C₅-C₁₀)arylcarbonyl,(C₅-C₁₀)aryloxycarbonyl, (C₁-C₆)alkylsulfonyl, and (C₅-C₁₀)arylsulfonyl;each R³ is independently selected from the group consisting of:hydrogen, halo, halo(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl, (C₅-C₁₀)heteroaryl,(C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₅-C₁₀)heteroaryl-O—,(C₅-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, O₂N—, NC—, amino,Ph(CH₂)₁₋₆HN—, (C₁-C₆)alkyl HN—, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, amino(C═O)—, aminoO₂S—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[(((C₁-C₆)alkyl)-N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)-N]—, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₅-C₁₀)heteroaryl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)— and(C₁-C₆)alkyl-(C═O)—O—; where alkyl, alkenyl, alkynyl, phenyl,heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R³ isoptionally substituted by at least one substituent independentlyselected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo, H₂N—,Ph(CH₂)₁₋₆HN—, and (C₁-C₆)alkylHN—; s is an integer from one to five;and R⁶ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, (C₅-C₁₀)heteroaryl,(C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-(SO₂)—,phenyl-(SO₂)—, H₂N—(SO₂)—, (C₁-C₆)alkyl-NH—(SO₂)—,((C₁-C₆)alkyl)₂N—(SO₂)—, phenyl-NH—(SO₂)—, (phenyl)₂N—(SO₂)—,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₅-C₁₀)heteroaryl-(C═O)—,(C₅-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₅-C₁₀)heterocyclic-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,phenyl-NH—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,((C₁-C₆)alkyl)₂N—(C═O)—, (phenyl)₂N—(C═O)—,phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—,(C₅-C₁₀)heteroaryl-[((C₁-C₆)alkyl)-N]—(C═O)—,(C₅-C₁₀)heterocyclic-[((C₁-C₆)alkyl)-N]—(C═O)—, and(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)-N]—(C═O)—; where alkyl, alkenyl,alkynyl, phenyl, benzyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy,phenoxy, amino of R⁶ is optionally substituted with at least one moietyindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, benzyl, (C₅-C₁₀)heterocyclic, (C₅-C₁₀)heteroaryl,(C₁-C₆)alkyl-SO₂—, formyl, NC—, (C₁-C₆)alkyl-(C═O)—,(C₃C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₅-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₅-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₅-C₁₀)heterocyclic-NH—(C═O)—, (C₅-C₁₀)heteroaryl-NH—(C═O)—,((C₁-C₆)alkyl)₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)-N]—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₅-C₁₀)heterocyclic-O—, (C₅-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₅-C₁₀)heterocyclic-(C═O)—O—, (C₅-C₁₀)heteroaryl-(C═O)—O—, O₂N—, amino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₅-C₁₀)heterocyclic-(C═O)—NH—, (C₅-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—, phenyl-(C═O)—[(C₁-C₆)alkyl-N]—,(C₁-C₆)alkyl-SO₂NH—, (C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—,(C₅-C₁₀)heterocyclic-SO₂NH— and (C₅-C₁₀)heteroaryl-SO₂NH—; wherein thephenyl or heteroaryl moiety of a R⁶ substituent is optionally furthersubstituted with at least one radical independently selected from thegroup consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,perfluoro(C₁-C₆)alkyl and perfluoro(C₁-C₆)alkoxy, with the proviso thatR¹ is not a naphthyl or phenyl; and with the proviso that when R¹ is aphenyl fused with an aromatic or non-aromatic cyclic ring of 5-7 memberscontaining up to three N atoms, said N is other than —NH or —NC₁₋₆alkylor if said N is —NH or —NC₁₋₆alkyl, then R¹ must be further substituted;and with the proviso that when R¹ is a phenyl fused with an aromatic ornon-aromatic cyclic ring of 5-7 members containing 1-3 heteroatomsindependently selected from O and S, then R¹ must be furthersubstituted.
 2. A compound of claim 1, wherein R¹ is


3. A compound of claim 1, wherein R¹ is


4. A compound of claim 1, wherein R¹ is


5. A compound of claim 1, wherein R¹ is


6. A compound of claim 1, wherein R¹ is


7. A compound of claim 1, wherein R¹ is


8. A compound of claim 1, wherein R¹ is


9. A compound of claim 1, wherein s is one to two; R³ is hydrogen or(C₁-C₆)alkyl; and R⁶ is H, (C₁-C₆)alkyl, or (C₃-C₁₀)cycloalkyl.
 10. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 11. A method of preventing ortreating a TGF-related disease state in an animal or human comprisingthe step of administering a therapeutically effective amount of acompound of claim 1 to the animal or human suffering from theTGF-related disease state.
 12. A method of claim 11, wherein saidTGF-related disease state is selected from the group consisting ofcancer, glomerulonephritis, diabetic nephropathy, hepatic fibrosis,pulmonary fibrosis, intimal hyperplasia and restenosis, scleroderma, anddermal scarring.